The lungs are a target of a number of acute viral pathogens. Of these, hantaviruses such as the Sin Nombre virus (SNV) represent a significant emerging infectious disease concern and are considered as high priority (Category A) agents for the NIAID biodefense initiative. A major concern is the lethality of these viruses. In Europe and Asia, infections frequently cause a hemorrhagic fever with renal syndrome (HFRS) with a mortality rate of 1-15%. However, in the Americas, infections are the cause of a severe hantavirus pulmonary syndrome (HPS), which leads to pulmonary failure and death in as many as half of the cases. Studies have demonstrated marked accumulations of viruses and extremely high levels of viral antigens in the lungs of HPS patients, consistent with their involvement in the deterioration of lung function. Despite a growing understanding of hantavirus infections, definitive treatments are lacking. To bridge this gap, the focus of our exploratory/developmental (R21) investigations is on the analysis and development of therapeutic approaches to block hantavirus replication in lung cells. Using newly developed assays, we will evaluate the effects of available and of novel antiviral agents, as follows: [unreadable] 1. Analysis of nucleoside inhibitors of hantavirus replication: Candidate nucleoside inhibitors of hantaviruses will be evaluated to identify potential immediately available antivirals, and to establish a basis for comparison with alternative inhibitors. [unreadable] 2. Characterization of interferon-induced virus inhibition: Interferon alpha (IFNa) will be tested in the absence and presence of nucleoside analogues to assess its effects. [unreadable] 3. Examination of novel phosphorodiamidate morpholino oligomer (PMO) antiviral activities: Antisense PMOs targeting virus transcription and translation initiation will be examined. [unreadable] We believe that these exploratory studies have a high probability of leading to more efficient treatment of hantavirus-mediated pulmonary failure. [unreadable] [unreadable]